Cheng A.N.Fan C.-C.Lo Y.-K.Kuo C.-L.Wang H.-C.Lien I.-H.Lin S.-Y.Chen C.-H.Jiang S.S.Chang I.-S.Juan H.-F.Lyu P.-C.Lee A.Y.-L.2020-01-222020-01-22201720452322https://scholars.lib.ntu.edu.tw/handle/123456789/452357Cdc7-Dbf4 kinase plays a key role in the initiation of DNA replication and contributes to the replication stress in cancer. The activity of human Cdc7-Dbf4 kinase remains active and acts as an effector of checkpoint under replication stress. However, the downstream targets of Cdc7-Dbf4 contributed to checkpoint regulation and replication stress-support function in cancer are not fully identified. In this work, we showed that aberrant Cdc7-Dbf4 induces DNA lesions that activate ATM/ATR-mediated checkpoint and homologous recombination (HR) DNA repair. Using a phosphoproteome approach, we identified HSP90-S164 as a target of Cdc7-Dbf4 in vitro and in vivo. The phosphorylation of HSP90-S164 by Cdc7-Dbf4 is required for the stability of HSP90-HCLK2-MRN complex and the function of ATM/ATR signaling cascade and HR DNA repair. In clinically, the phosphorylation of HSP90-S164 indeed is increased in oral cancer patients. Our results indicate that aberrant Cdc7-Dbf4 enhances replication stress tolerance by rewiring ATR/ATM mediated HR repair through HSP90-S164 phosphorylation and by promoting recovery from replication stress. We provide a new solution to a subtyping of cancer patients with dominant ATR/HSP90 expression by combining inhibitors of ATR-Chk1, HSP90, or Cdc7 in cancer combination therapy. ? 2017 The Author(s).[SDGs]SDG3ATM protein; ATM protein, human; ATR protein, human; CDC7 protein, human; cell cycle protein; Clk dual-specificity kinases; DBF4 protein, human; heat shock protein 90; protein serine threonine kinase; protein tyrosine kinase; tumor marker; apoptosis; case control study; cell proliferation; DNA replication; follow up; gene expression regulation; genetics; human; metabolism; mouth tumor; pathology; phosphorylation; physiological stress; signal transduction; squamous cell carcinoma; tumor cell culture; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Biomarkers, Tumor; Carcinoma, Squamous Cell; Case-Control Studies; Cell Cycle Proteins; Cell Proliferation; DNA Replication; Follow-Up Studies; Gene Expression Regulation, Neoplastic; HSP90 Heat-Shock Proteins; Humans; Mouth Neoplasms; Phosphorylation; Protein-Serine-Threonine Kinases; Protein-Tyrosine Kinases; Signal Transduction; Stress, Physiological; Tumor Cells, Culturedjournal article10.1038/s41598-017-17126-22-s2.0-85037062839https://www2.scopus.com/inward/record.uri?eid=2-s2.0-85037062839&doi=10.1038%2fs41598-017-17126-2&partnerID=40&md5=5dbb539ef20c4c34a8d7d929d5f97c87